Adoptive-cell-transfer therapy for the treatment of patients with cancer

Abstract

Adoptive immunotherapy--the isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration--is a promising approach to inducing antitumour immune responses. The molecular identification of tumour antigens and the ability to monitor the persistence and transport of transferred cells has provided new insights into the mechanisms of tumour immunotherapy. Recent studies have shown the effectiveness of cell-transfer therapies for the treatment of patients with selected metastatic cancers. These studies provide a blueprint for the wider application of adoptive-cell-transfer therapy, and emphasize the requirement for in vivo persistence of the cells for therapeutic efficacy.

Figure 1. Mechanisms that limit immune responses

Many mechanisms could account for the limited effectiveness of endogenous or vaccine-induced immune responses to tumours. a | Inadequacies of the afferent stages of an antitumour immune response might include a lack of helper T cells, non-activated antigen-presenting cells (APCs), or active suppression by CD4⁺CD25⁺ regulatory T cells. b | The CD8⁺ cytotoxic T lymphocytes (CTLs) could be insufficient in number, or deficient in T-cell-receptor avidity or receptor signalling, or express sub-optimal function (low lysis or T-helper-2-cell polarized cytokine release). c | The efferent phase of the immune response might be blocked by mechanisms including failure of T cells to traffic to tumour sites, production of immunosuppressive factors by the tumour, or CTL apoptosis on encountering tumour cells. d | Finally, the tumour cells might acquire resistance to CTL attack through loss of tumour-antigen expression, loss of human-leukocyte antigen (HLA) expression, acquisition of resistance to CTL lysis, or loss of capacity for apoptosis.

Figure 2. Tumour regression by adoptive-cell-transfer therapy

Activated T cells can mediate the regression of a large excess of metastatic melanoma. Computed tomography scans of the trunk and pelvis of one patient document the regression of bulky metastases (arrows) in axillary (top), pelvic (middle) and mesenteric (bottom) lymph nodes, mediated by adoptive-cell-transfer therapy following non-myeloablative but lymphodepleting chemotherapy. Tumour deposits were present before treatment and substantially shrank or completely resolved when evaluated 8 months later.